Actions of nitric oxide (NO)

Concentric Vs. Eccentric LVH.

Concentric: normal mass but increased relative all thickening.
Eccentric: Increased mass but no increase in relative wall thickness.
Concentric occurs in AS.
Eccentric occurs in AR.

Source

Dead space

Total dead space (i.e physiological dead space) = anatomical dead space + alveolar dead space.

• Alveolar dead space is measured by subtracting anatomic dead space from physiologic dead space.
• West zone 1 contains alveolar dead space. The amount of this space is minimal under normal conditions.
  
  Physiological dead space is measured using the Enghoff modification of Bohr's equation, using arterial CO2 instead of exhaled CO

Anatomic dead space is Measured by Fowler's method.

The ratio of physiologic dead space to tidal volume is usually about 1/3. Source

Factors increasing dead space:
Source

• Body size: anatomic dead space is about 2ml / Kg for adult and 3ml/Kg in infancy.
• General anesthesia – multifactorial, including loss of skeletal muscle tone and bronchoconstrictor tone
• Anesthesia apparatus/circuit
• Artificial airway
• Neck extension and jaw protrusion (can increase it twofold)
• Positive pressure ventilation (i.e. increased airway pressure)
• Upright posture as opposed to supine (because of decreased perfusion to the uppermost alveoli) (increases the alveolar dead space, not anatomic dead space)
• Pulmonary embolus, PA thrombosis, hemorrhage, hypotension, surgical manipulation of pulmonary artery tree – anything that decreases perfusion to well-ventilated alveoli
• Emphysema (blebs, loss of alveolar septa and vasculature)
• Age
• Anticholinergic drugs
• Anatomic dead space appears to increase with height and does not change with sex. Source

Alveolar dead space is increased by :

• Poor cardiac output
• Parynchymal lung disease
• High positive pressure ventilation
• Pulmonary vascualr occlusion
• Upright posture

• Haemorrhagic pulmonary metastases -> choriocarcinoma and angiosarcoma. (mnemonic: placenta is vascular, angiosarcoma has angio in the name)
• A miliary pattern of metastases is visualised with renal cell carcinoma and malignant melanoma. (m for melaona, renal -> canon ball metz in uniform distribution)

loss of nitric oxide production, termed endothelial dysfunction, is the earliest event in the development of hypertension. Source

• lipohyalinosis occurs because of the effects of hypertension and subintimal foam cells but it is not the same as hyaline arteriolosclerosis.

| Erosion | loss of Superficial epidermis => NO SCARRING | | |

Skin cancer

Squamous cell CA	Basal Cell carcinoma	Maligant melanoma
Chronic non healing ulcers or firm pink rapidly growing size	Pearly, flesh coloured lesion with rolled up edges, central depression and telangiectasia. Occurs in sun exposed areas AKA Rodent ulcer	ABCDE lesions
Rapidly growing	Slow growing. Arises from keratinocytes. "only rarely a threat to life"	The most dangerous skin cancer; use ABCDE as warning signs. Arises from melanocytes which are neural crest derivatives
Metastasis is uncommon. (upto 5%)		Metastasis common. (Nodes and distant). 5 year survival for nodal mestastasis is only 10%.
RF: Sunlight, smoking, chronic ulcers,
Occurs on areas of ⬆ sun exposure
Rx: Excission with 4mm margins.
Mohs micrographic surgery in high risk / cosmetically sensitive areas.
Poor prognosis if > 20mm wide or > 4mm deep

Actinic keratosis

Actinic keratosis is a premalignant lesion which can transform into squamous cell carcinoma.
The image below shows "Malignant transformation of actinic keratoses to squamous cell carcinoma"

Inhibition : Somatostatin

• Peak GH secretory activity occurs within an hour after the onset of deep sleep (i.e in Non-rem sleep).
  

• Effects of growth hormone on carbohydrate metabolism
  • Growth hormone causes lipolysis -> releases FFA -> which produces ketone bodies which are a ready source of energy for tissues during starvation, hypoglycaemia and stress.
  • Decreases glucose uptake into some tissues.
  • It sensitizes the pancreas to insulin secreting stimuli but does not directly increase insulin secretion.
  • Promotes gluconeogenesis and glygogenolysis in the liver.
  • Glucagon causes hyperglycaemia and reflex insulin mediated hypoglycaemia which griggers GH release. Safer than direct insulin mediated hypoglycaemia.

[!INFO] However, Sri Lankan guidelines recommend starting with dual low dose combination.

Causes of isolated systolic hypertension

Pharmacology of antihypertensives

Patients with resistant hypertension are more likely to have secondary causes. (which may contribute atleast partly).

[!INFO] "Renal parenchymal diseases"
The most common renal parenchymal diseases leading to secondary hypertension include

1. diabetic nephropathy, chronic glomerulonephritis, glomerulosclerosis, and autosomal dominant polycystic kidney disease (ADPKD)
2. and all these disorders result in chronic kidney disease (CKD). Source
3. 

Clinical entities to consider in secondary causes for hypertension:

1. Renal parenchymal disease
2. Endocrine disease
3. Reno-vascular hypertension
   • Consider when patients have uncontrolled hypertension, have renal bruit, and develop deterioration of renal function after taking angiotensin-converting enzyme (ACE) inhibiting drugs. Ultrasound renal Doppler is the initial recommended test for the screening and diagnosis
4. Vascular and other
   1. Coarctation of the aorta
   2. OSA

There is a large overlap with 'causes of secondary hypertension'.
Causes of resistant hypertension
5. OCP

3 options with varying disadvantages:

• Splenectomy - single step cure but immunosuppresive, surgical risks.
• Rituximab - also immunosuppresive; short drug course but not need or surgery
• Thrombopoietin receptor agonists (romiplostim, eltrombopag) - not immunosuppresive but long term drug use required.

High fevers with delirium.

Early in disease course, fever occurs at irregular intervals each day.
Later in the course of infection, rupture of infected red cells can become synchronous following concurrent schizont rupture and release of merozoites from erythrocytes.

Febrile paroxysms may occur every other day (tertial) for P. vivax, P. ovale, and P. falciparum and every third day for P.malariae. Paroxysms occurring at regular intervals are more common in the setting of infection due to P. vivax or P. ovale than P. falciparum..

Fever in falciparum is usually irregular - Source
[!TIP] Mnemonic: "m" = 3 lines. P malariae causes fever every 3rd day.

• Tertian fever: This occurs every 48 hours
• Quartan fever: This occurs every 72 hours

Labs:

• Even in uncomplicated malaria there will be
• <0.1% parasitized red blood cells
• anaemia, thrombocytopenia
• elevated transaminases
• mild coagulaopathy
• elevated BUN and creatinine

Chronology of malaria

• Sporozoites from mosquito bite migrate to the liver within one to two hours!.
• Patient is asymptomatic for 12 to 35 days. (i.e one and a half weeks)
• Symptoms begin during the erythrocytic stage when RBCs rupture.
• Relapses of vivax and ovale tend to occur within 2 to 3 years of infection.

Severe paracitaemia = > 5% of cells area affected.
90% of severe malaria is due to falciparum. However, vivax and knowlesi can cause severe malaria. - UpToDate

Manifestations

• impaired conciousness - GCS < 11
• Prostration - weakness which prevents sitting, walking or standing.
• Multiple convulsions - >2 within 24 hours.
• Acidosis - HCO3 < 15 (Base deficit > 8) or Venous lactate > 5.
• Hypoglycaemia
• Severe malarial anaemia (Hb < 5)
• Renal impairment
• Jaundice – Plasma or serum bilirubin >50 mcmol/L (3 mg/dL) with a parasite count >100,000/mcL (approximately 2 percent)
• Pulmonary oedema
• Significant bleeding (nose, gums, venepuncture sites)
• Shock
• Hyperparasitaemia

  • 5% for Falciparum malaria

• Hepatic failure (UpToDate)

Liver dysfunction does occur in malaria but wasn't included in the list above. (??because it's common and doesn't occur only in severe malaria)

• Liver dysfunction - mild jaundice due to haemolysis is common.
  • Severe jaundice due to hemolysis, hepatocyte injury, and cholestasis may occur in the setting of P. falciparum infection

Treatment for severe malaria is IV or IM Artesunate

📑📑Video
- causes constriction - miosis; begins at the Edinger-Westphal nucleus near the occulomotor nerve nucleus. The fibers enter the orbit with CNIII nerve fibers and ultimately synapse at the cilliary ganglion.

Action potentials

[!INFO] Inactivated sodium channels
In the aboslute refractor periods the sodium channels are in the "inactivated" state (not the closed state)
When the relative refactor period begins, the sodium channels are starting to return to their closed state.
mnemonic: the "closed state" means the channels are "primed" to fire.

Apparently, ARP lasts into the first 1/3 of the repolarization phase: Source-YouTube

• Absolute refractory period is caused by sodium channel inactivation.
• Relative refractory period is caused by one of both of the following: (1) some Na+ channels remain in the inactive state; (2) an increased number of K+ channels are open. Source

MRI is the modality of choice for delineating perianal fistulae in Crohn's disease.

• steroids - oral or IV
  • IV steroids are used for severe disease in CD. Source
• Azathioprine, mercaptopurine and MTX can also be used. (as addon therapy, not as monotherapy)
  • A liquid based formula given orally or via NG tube. Helps to induce remission.
    "Thiopurines" in the diagram are are mercaptopurine and azathioprine.
  • sulfasalazine molecules = mesalazine--AZO-bond--sulfapyridine.
  • Gut bacterial break down the azo bond to release active mesalazine in the colon (large intestine)

- *encystation* for continuation of the infective cycle occurs in the large intestine. 
- 90% of infected individuals show asymptomatic colonization but they still shed infective cysts. 

• Liver abscess (commonest extraintestinal manifestation)
  • 95% of people who develop amoebic abcess, do so within 5 months
  • Less than 1/3 of patient having an amoebic liver abscess have active diarrhoea.
  • Younger patients tend to present acutely; (eg; hiker / camper)
    • older patients in endemic areas present subacutely with symptoms of weight loss and hepatomegaly over 6 months. (old man in rural village)
  • Presents with Right Upper Quadrant pain which radiate to the shoulder.
  • Right sided pleural effusion is common.
  • Presents with high swinging fever, hepatomegaly.
  • can rupture into pleural space -> Amoebic empyema
  • Physical examination:
    • point tenderness over the liver
    • #hepatomegaly
    • Jaundice is rare.
  • Investigations:
    • In amoebic liver abscess, there is leukocytosis without eosinophilia.
    • ALP elevation is commoner than AST / ALT elevation. (Elevated ALP (in 80%) and ALT and AST may also be elevated. (UpTodate))
• "stool microscopy may show trophozoites if examined within 15 minutes or kept warm (known as a 'hot stool')" - when stool cools, amoeba encyst and then pathogenic and non pathogenic species cannot be distinguished. Trophozoites are easily killed by water, drying, barium. So at least 3 samples of stool must be examined.
  • Motile trophozoites containing red cells ("hematophagous trophozoites are diagnostic")
• Colonic biopsy from a lesion can show trophozoites but carries high risk of perforation .
• Amoebic liver abscess aspirate will not show trophozoites because they live in the abscess capsule and not the necrotic center.
• • Or diloxanide furoate.
    | :--------------------------------------: | :--------------------------: | ------------------------------------------------------------------------------------------ |
    | Metronidazole / paromoycin | Tinidazole / metro | TMP + SMX |

Meropenem penetration: Meropenem is not absorbed after oral administration. It penetrates well into most body fluids and tissues, including CSF, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria

| All are neurotoxic except | hump nosed and saw scaled viper |
| Local swelling and necrosis NOT seen | Kraits and sea snakes |

• The common krait - Bungaru caeruleus - has a powerful neurotoxin.
• Bites are painless and often occur during sleep.
• It characteristically causes a descending paralysis.
• The venom contains a presynaptic toxin which irreversibly inhibits neurotransmission due to it's phospholipase A2 action.
• Patients can have respiratory failure requiring intubation within 7 hours.
• Antivenom will 'mop-up' venom in the blood stream but will not reverse paralysis.
• Paralysis usually resolves in about 4 days with complete EMG resolution taking about 6 weeks.
• Resolution of paralysis progresses upwards.
• Mnemonic: "Shut down and power up"
• No chronic neurological deficits were reported.

[!TIP] HNV => VICC; but no overt bleeding, plantations, severe local pain+, Acut kidney injury

• Highly venomous. Dry bites are uncommon!
  • It also has weak myotoxic, neurotoxic and nephrotoxic effects.
• 90% have severe local pain, swelling and necrosis.
• Commonest systemic effects are VICC - venom induced consumption coagulapathy (venom has a procoagulant effect) and AKI - but overt bleeding usually doesn't occur.
  • Multifactorial mechanisms.
  • Causes acute tubular necrosis or FSGS.
• Local effects: haemorrghagic blister at bite site and local lymphadenopathy. but not a unique feature
• Other complications:
  • TTP, HUS, bradycardia , ischemic or haemorrghagic stroke.
• The main cause for death following hump nosed viper bite is
  • Coagulopathy (prolonged WBCT20 is taken as indications of systemic envenomation)
  • or nephrotoxicity (which can be mild or severe, requiring dialysis)
• FBC - eosinophilia is predominant.

VICC

VICC is NOT the same as DIC. Source
In contrast to DICC, VICC has the following.

• VICC -> no evidense of systemic microthrombi
• No end organ failure
• VICC has rapid onset and resolution
• In DICC, thrombin generation is mediated by the tissue factor / VIIa pathway. In VICC, its ??mediated by venom??

- Non shockable rhythm: ***Adrenaline 1mg ASAP*.** **(10ml of 1:10,000 IV or 1ml of1:1000 IV)**